Chlamydia trachomatis is a major infectious bacterial agent that causes sexually transmitted disease (STD) worldwide. In the United States 1,108,374 Chlamydia infections were reported to the Centers for Disease Prevention and Control in 2007. Complications in women include pelvic inflammatory disease, ectopic pregnancy and involuntary tubal factor infertility. Recent studies have discovered that decreasing the infection through antimicrobial treatment increases the re-infection rate in humans and may actually exacerbate the pathology within the reproductive tract. These findings highlight the need for an effective vaccine against genital Chlamydia infection. A major challenge in Chlamydia vaccine efforts is to understand the immune regulatory mechanisms governing the protective versus the pathogenic responses. The main objective of this proposal is to define the roles of immunomodulatory molecules produced by IL-10 deficient DCs in promoting a protective immune response against genital Chlamydia infection and eliminating the immunopathology associated with the infection. The knowledge of the mechanism of action of such molecules could lead to targeted immunomodulatory strategies in designing drugs and efficacious vaccines against Chlamydia. We will accomplish these objectives using 2 specific aims. Aim 1: To define the role of alpha-enolase and fatty acid-binding protein up-regulated in Chlamydia-pulsed IL-10 deficient DCs in the protective immune response against genital Chlamydia infection. Our working hypothesis is that molecules up-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in rapid DC maturation and Th1 cell activation. Study proposal are; a). To investigate the role of alpha- enolase and fatty acid-binding protein in DC acquisition of maturation markers and enhanced APC function in vitro. b). To investigate the cell signaling mechanism of immunestimulatory action of alpha-enolase and fatty acid-binding protein in vitro and in vivo. Aim 2: To define the role of apoptosis-associated speck-like protein containing a CARD (ASC) down regulated in Chlamydia-pulsed IL-10KO BMDCs in protecting against the pathological immune responses during a Chlamydia infection in vivo and in vitro. Our working hypothesis is that molecules down-regulated in Chlamydia-pulsed IL-10 deficient DCs play a rule in pathological immune responses. Study proposal are; a). To investigate of the role of ASC DC acquisition of maturation markers and enhanced APC function and the pathogeneses of Chlamydia induced tube pathology and infertility. b) To investigate the role of ASC in the immunoregulatory function of DCs. Results from these studies will aid in the development of drugs and vaccines against Chlamydia, which will have significant implications for controlling and preventing genital Chlamydia infections and sequelae. PUBLIC HEALTH RELEVANCE: The main objective of this proposal is to define the roles of immunomodulatory molecules produced by IL-10 deficient DCs in promoting a protective immune response against genital Chlamydia infection and eliminating the immunopathology associated with the infection.